This application proposes to investigate the significance of antiphospholipid-protein antibodies (aPL-P) and ischemic stroke, specifically recurrent ischemic stroke and other thrombotic events. We will assay 2 aPL-P serum biomarkers currently used in clinical practice, with the goal to develop a battery ("portfolio") of immune-mediated increased thrombosis risk. Sera have already been collected and are currently being stored. We will use data from a previously conducted 2-year, double-blind, NTH/NINDS funded, clinical stroke prevention trial of warfarin versus aspirin (WARSS). aPL-P is the most commonly identified biomarker of immune-mediate thrombosis. The aim of this proposal is to identify new, emerging, and potentially more specific and sensitive biomarkers of aPL-P immunoreactivity that may more accurately predict a high-risk group of ischemic stroke patients for recurrent thrombosis. Thrombosis and ischemic stroke are chronic, disabling, and complex diseases that often involve immune/inflammatory mechanisms. This proposal will allow us to better clarify the role of these biomarkers m recurrent thrombosis and ischemic stroke in this unique, large, prospectively studied cohort. No other data set exists to answer this important question. Using a single experienced laboratory, we will test 1,770 subjects from the WARSS/APASS collaborative study for antibodies to the aPL-P cofactor - beta 2 glycoprotein-I (also known as apolipoprotein H) and antibodies to phosphatidylserine (aPS), the two most promising, new aPL-P biomarkers. Our preliminary data suggest that these biomarkers may be associated with a higher risk of recurrent events than the original aPL-P biomarkers (LA and aCL). Subjects with a specific portfolio of aPL-P positivity, have higher event rates over the subsequent 2 years than those who are positive for LA or aCL only, two of the most commonly clinically tested aPL-P. Further, the portfolio may improve specificity, positive predictive value, and efficiency of predicting a subgroup of aPL-P+ patients at high risk for recurrent thrombo-occlusive events. Our primary goal is to perform multivariable analyses to determine whether a specific battery of aPL-P are independent predictors of future strokes and thrombo-occlusive events. If a high-risk group can be confirmed, innovative pilot clinical trials can be initiated. The proposal will involve investigators already collaborating for many years together at: The Mount Sinai School of Medicine, University of Texas - San Antonio, and the Medical University of South Carolina.